Journal of Agricultural Science, Cambridge (1990), 115, 155-162. Printed in Great Britain 155 REVIEW Ketogenesis in the liver of ruminants - adaptations to a challenge V. A. ZAMMIT Hannah Research Institute, Ayr, Scotland, KA6 5HL, UK INTRODUCTION The descriptive aspects of hepatic fatty acid metab- olism, and of ketogenesis in particular, have been extensively described for ruminants. There is, how- ever, a distinct lack of information on the more mechanistic aspects of the subject. The biochemical profile of the livers of ruminant species shows both similarities to, and striking differences from, that of simple-stomached animals. Consequently, it may not always be valid to extrapolate from the situation in, say, rat liver to that in ruminant liver in order to interpret experimental observations in ruminants. Of perhaps greater interest is the recognition that the adaptations in the ruminant system are important not only in enabling us to rationalize the physiological changes observed in ruminants, but are in themselves of interest in the analysis of metabolic regulatory strategies. Consequently, this review deals with the peculiarities of the regulation of hepatic ketogenesis in ruminants, and the biochemical mechanisms that may explain their existence. Aetiology of ketosis It is possible, under experimental conditions, to distinguish between the roles of long-chain fatty acid delivery to the liver (i.e. mobilization from adipose tissue) and intrahepatic direction of fatty acids towards ketone body formation. Thus, peripheral, intravenous infusion of fatty acids into fed sheep does not result in the same increased rate of ketogenesis as observed when the experiment is performed on starved animals (Bergman 1968), suggesting that mere avail- ability of fatty acids is not sufficient to elicit major oxidation of long-chain fatty acids. Similarly, although the concentration of plasma nonesterified fatty acids (NEFA) is increased equally in non- lactating and lactating cows by several days' star- vation, the ketogenic response is several times higher in lactating animals (Baird et al. 1979). These observations demonstrate that, although the hor- monal conditions that characterize any physiological condition always enable the liver and adipose tissue to act in concert, intrahepatic mechanisms of regulation of ketogenesis are of major importance during the induction of ketosis. In agreement with this, it has been shown experimentally that, during the devel- opment of starvation- or diabetes-induced ketosis in rats, it is the metabolic state of the liver that largely determines the rate of ketone formation (Grantham & Zammit 1986, 1988). In contrast, during reversal of these conditions, it is the supply of fatty acids from adipose tissue that may be the controlling factor. Although the exact identity of the controlling step may appear to be of academic interest in as much as clinical symptoms of ketosis in ruminants can be effectively counteracted by administration of anti- lipolytic agents (see Baird 1977), the question may be relevant with respect to treatments that alter the hormonal status of the animal, e.g. injection of somatotrophin. In this instance it is possible that, if animals are only in marginal negative energy balance, a greater rate of lipolysis in adipose tissue may not be accompanied by increased ketogenesis in the liver. In fed ruminants, the major substrate for hepatic ketogenesis is likely to be butyrate. During periods of ketosis, however, when the animal mobilizes in- creasing amounts of NEFA from adipose tissue, long- chain fatty acids are the important substrates es- pecially if butyrate supply from the gut is diminished because of inappetance. Consequently, the regulation of long-chain acylcarnitine synthesis in the extra- mitochondrial compartment is of major importance. The limitations placed on the use of long-chain fatty acids for oxidation are thought to include those imposed by the competing process of acylglyceride synthesis (Zammit 1984). Although in ruminants the rate of lipoprotein secretion by the liver is very low (Klepp et al. 1988), the rate of fatty acid esterification to glycerol can be considerable in isolated sheep hepatocytes incubated with high concentrations of fatty acid (Lomax et al. 1983). The relative ease with which ketonaemic ruminants acquire a fatty liver suggests that this may also occur in vivo. Whether the rate of long-chain fatty acid oxidation is saturated at 6-2